ABSTRACT This application is in response to the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) program announcement PAR-18-423 for implementing a multi-center randomized clinical trial to test the hypothesis that treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy in people with prediabetes will reduce the progression to type 2 diabetes mellitus (T2DM). For the U34 planning phase, we have established a network of ten clinical sites guided by an experienced team of investigators with an extensive background in conducting multicenter randomized trials. To provide leadership for the trial, we have built a consortium of exceptional investigators and include the following: (a) The Center for Clinical Trials at the Johns Hopkins University Bloomberg School of Public Health to establish a central Data Coordinating Center; (b) The Clinical Research Center for Sleep at the University of Pennsylvania to organize a Sleep Reading Center for home sleep testing; (c) a PAP adherence core; (d) a weight loss core at Brown University; and (e) a bioassay core laboratory at the University of Minnesota. In this application, we describe our record of conducting and managing multi-center research programs; strategies for assembling and managing a complex research network; and the talented team of coinvestigators with expertise in pulmonary and sleep medicine, endocrinology, clinical trials methodology, weight loss interventions, epidemiology, and biostatistics. The Specific Aims for the U34 planning period are to: (1) refine the organizational structure and the leadership plan for the trial; (2) finalize the study protocol and associated source documents, provide clinical site training, and develop a manual of operations for the Sleep Reading Center, the PAP Adherence Core, and the Clinical Sites; (3) construct a data management system, establish methods of data quality assurance, and develop a manual of operations for the DCC; (4) outline plans for data analysis and handling of study-related publications and presentations; and (5) obtain human subjects and regulatory approvals from a central IRB. The U34 consortium will develop a U01 grant application for a multi-center clinical trial on the utility of PAP therapy in preventing T2DM in people with OSA and prediabetes. The Specific Aims of the U01 trial are as follows. Aim 1: To determine whether, in people with prediabetes and moderate-to-severe OSA, the addition of PAP therapy to a lifestyle intervention is associated with lower rate of progression from prediabetes to T2DM. Aim 2: To assess whether, in people with prediabetes and moderate-to-severe OSA, the addition of PAP therapy to a lifestyle intervention program is associated with greater improvements than with lifestyle intervention alone in: (a) insulin sensitivity, as assessed by the homeostasis model assessment index (HOMA-IR); (b) hemoglobin A1c modeled as a continuous variable; (c) sympathetic nervous system activity; (d) inflammatory markers including C-reactive protein (CRP) and interleukin-6 (IL-6); (e) resting blood pressure; (f) body weight and measures of central obesity (i.e., waist circumference); and (g) OSA-related symptoms and quality of life.